The broad long-term objective of the proposed research is to investigate the potential efficacy and safety of new cell based therapy for the treatment of pulmonary hypertension (PH). The disorder is a serious life threatening disease characterized by elevated pulmonary arterial pressure, right heart failure and pulmonary vascular remodeling. Pharmacologic therapy can improve survival and quality of life. However, the long term outcome is not favorable. Gene therapy has a beneficial effect in experimental models of PH. However, the use of viral and nonviral vectors has led to low level gene transfer, random expression and adverse effects such as an inflammatory response that limits the clinical utility of this approach. Another approach for the treatment of PH is the use of cell based therapy. It is our hypothesis that wild type (unmodified) and gene modified mesenchymal stem cells (MSCs) will have a beneficial effect in experimental models of PH. This hypothesis was tested in rats with monocrotaline induced PH using well-characterized expanded MSCs. The results of this recently published study show that intratracheal administration of unmodified rat MSCs 2 weeks after monocrotaline administration attenuates monocrotaline induced PH and improves endothelium dependent responses 5 weeks after the administration of the plant alkaloid. These data provide proof of concept and are the basis of this application on lung stem cell biology and cell based therapy for the treatment of pulmonary hypertension. The overall objective of the proposed research is to investigate the potential efficacy and safety of MSC therapy in experimental PH. The first specific aim is to investigate the effect of unmodified and gene modified MSCs on pulmonary arterial and wedge pressure and cardiac output and on pulmonary vasodilator response to acetylcholine for periods up to 6 months after moncrotaline administration. These studies will provide information on efficacy and safety of the cell based therapy. The second specific aim is to investigate the fate of intratracheally injected MSCs in the lung for periods up to 6 months. These studies will examine the localization and phenotype of transplanted MSCs and the potential to induce tumor formation in the lung using light microscopy and immunohistochemical techniques.